Epidemiological studies show that oestrogen reduces the risk of colorectal cancer in postmenopausal women and ERbeta (oestrogen receptor beta)-selective ligands have been reported to be very effective treatment in animal models of inflammatory bowel disease. Several studies have shown that ERbeta is the predominant ER in the colonic epithelium, but it is not clear whether the benefit of ERbeta agonists in inflammatory bowel disease are due to their action on the colon epithelium itself, or on the immune system. In order to address this issue, we have compared colons of ERbeta(-/-) and wild-type mice with regard to morphology, histology, proliferation and differentiation. We found that the number of proliferating cells was higher in ERbeta(-/-) mice, and the migration of labelled cells from base to lumen of the crypts was faster. Additionally, immunohistochemical staining revealed fewer apoptotic cells (cleaved caspase 3-positive), a significant decrease in expression of the epithelial differentiation marker, cytokeratin CK20, the adherens junction protein, alpha-catenin, and the hemidesmosomal protein, plectin, in ERbeta(-/-) mice. These findings suggest a role for ERbeta in growth, organization and maintenance of the normal colonic crypt-villus architecture. The next step is to elucidate the molecular mechanisms that underlie the signalling of ERbeta in normal cell growth and assess whether or not ERbeta agonists will be useful drugs in the prevention or treatment of colorectal cancer. Dietary phyto-oestrogens are believed to play a role in protection against colorectal cancer. Lignans, such as enterolactone, an ER agonist, prevent cancer development in animal models. Since ERbeta is the only ER in the colon, there is enough reason to speculate that phyto-oestrogens are acting through ERbeta.